Abstract 4348059: Genetic Variants Drive Phenotypic Diversity and Adverse Outcomes in Left Ventricular Hypertrabeculation

Abstract

Background: Left ventricular hypertrabeculation (LVHT), often also known as left ventricular non-compaction, describes a cardiac phenotype characterized by prominent trabeculae and deep intertrabecular recesses. Genetic background of LVHT remains poorly understood. Moreover, the clinical relevance of genetic variants in LVHT has not been well described. Aims: This study aimed to characterize the genetic structure of a large LVHT cohort and investigate the impact of underlying genotype on clinical features and outcomes. Methods: Unrelated subjects with a cardiac magnetic resonance (CMR) - confirmed diagnosis of LVHT from four tertiary hospitals in China between 2010 and 2023 were prospectively included. Diagnosis of LVHT necessitated both the following CMR criteria: 1) long-axis (end-diastolic): a noncompacted (NC) /compacted(C) ratio >2.3 in ≥1 LV segments; 2) short-axis (end-diastolic): a NC/C ratio ≥3 in ≥1 of segments 1–3/7-16, or a NC/C ratio ≥2 in ≥1 of segments 4-6. Whole exome sequencing was conducted in all subjects. Primary endpoint was a composite of major adverse cardiovascular events (MACE). Cox proportional hazards model was used in statistical analysis. Results: A total of 406 subjects diagnosed with LVHT were included in the study. The median age at diagnosis was 38 years (IQR 26-52), with 67% males and 88% adults. Overall, 136 pathogenic (P) or likely pathogenic (LP) variants were found in 125 subjects (30.8%). TTN (13.8%) was the most common gene, followed by MYH7 (2.9%) and MYBPC3 (2.5%) (Figure 1). Subjects presented with at least 9 sub-phenotypes, the dilated being the most prevalent type (69.2%), followed by the benign type (7.4%), the hypertrophic type (5.7%), LVHT with congenital cardiovascular malformations (5.7%) (Figure 2A). TTN (19%) was the most prevalent gene identified in the dilated group, MYH7 and MYBPC3 (14%) were the most prevalent genes in the hypertrophic group (Figure 2B). During a median follow-up of 35.7 months, combined covariate analysis revealed that genotype-positive status was independently associated with MACE (HR: 1.69; 95% CI: 1.12-2.56; P =0.013) (Figure 3). Conclusions: LVHT possesses a heterogeneous nature, exhibiting diverse genetic and phenotypic profiling. Subjects with LVHT carrying P/LP variants have worse prognosis. Therefore, genetic testing may contribute to prognostic stratification and management guidance in these subjects.